Procyanidin B2 ameliorates endothelial dysfunction induced by nicotine via the induction of tetrahydrobiopterin synthesis

Smoking is an independent risk factor for the cardiovascular diseases. Nicotine, a major component of tobacco, is responsible for the impaired endothelial-dependent vasorelaxation in smokers. Procyanidin B2 (PCB2), a natural flavonoid, has been reported to possess several potential beneficial effects on the cardiovascular system. However, whether PCB2 prevents nicotine-induced endothelial dysfunction remains unknown. In this study, we demonstrated that PCB2 improved nicotine-impaired endothelium-dependent vasorelaxation in mouse thoracic aortas. Mechanistically, PCB2 increased the expression levels of dihydrofolate reductase (DHFR) and GTP cyclohydrolase 1 (GCH1), two important enzymes in the synthesis of tetrahydrobiopterin (BH₄), in mouse aortas and cultured ECs. GSK0660, a selective antagonist of peroxisome proliferator-activated receptor δ (PPARδ), abolished the PCB2-induced effects on BH₄ synthesis, nitric oxide (NO) production and vasodilation. Collectively, we demonstrated that PCB2 mitigates nicotine-induced endothelial dysfunction through a PPARδ-BH₄ dependent manner, thereby suggesting a novel role of PCB2 in preventing vascular dysfunction caused by nicotine exposure.